rs17110563

Positions:

• chr12-71972526-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173353.4(TPH2):​c.616C>T​(p.Pro206Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,092 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: TPH2 NM_173353.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 7.90

Genes affected

TPH2 (HGNC:20692): (tryptophan hydroxylase 2) This gene encodes a member of the pterin-dependent aromatic acid hydroxylase family. The encoded protein catalyzes the first and rate limiting step in the biosynthesis of serotonin, an important hormone and neurotransmitter. Mutations in this gene may be associated with psychiatric diseases such as bipolar affective disorder and major depression. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18247601).
• BS2: High AC in GnomAd4 at 160 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPH2	NM_173353.4	c.616C>T	p.Pro206Ser	missense_variant	6/11	ENST00000333850.4	NP_775489.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPH2	ENST00000333850.4	c.616C>T	p.Pro206Ser	missense_variant	6/11	1	NM_173353.4	ENSP00000329093	P1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00119 AC: 300 AN: 251428 Hom.: 0 AF XY: 0.00124 AC XY: 168 AN XY: 135892

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00153 AC: 2243 AN: 1461818 Hom.: 6 Cov.: 32 AF XY: 0.00155 AC XY: 1126 AN XY: 727218

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74468

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00155 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tryptophan 5-monooxygenase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Major depressive disorder;C2751802:Attention deficit-hyperactivity disorder, susceptibility to, 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 09, 2021

- -

Bipolar affective disorder, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.18	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.013	D
Polyphen		0.32	B
Vest4		0.72
MVP		0.63
MPC		0.87
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.70
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17110563; hg19: chr12-72366306;